Dissecting the virulence and antibiotic resistance potential of Klebsiella pneumonaie in disparate environments

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Klebsiella pneumoniae is ubiquitously distributed in the environment, including in water, soil, plants, insects, aquatic and agricultural animals, and humans. Due to its diverse ecological distribution and its ability to acquire antimicrobial resistance (AMR) genes through horizontal gene transfer, multi-drug resistant (MDR) K. pneumoniae is considered to be a major AMR trafficker. In contrast, hypervirulent K. pneumoniae has limited AMR genes but causes invasive infection. Even though AMR genes and virulence factors are both encoded by mobile genetic elements such as plasmids, we rarely observe convergence of these two phenotypes in one strain. One potential explanation based on genomic comparison of diverse K. pneumoniae is that the MDR and the hypervirulent lineages may prefer different ecological niches. However, there has not been a systematic comparison between MDR and hypervirulent strains to define their growth in different environments. Moreover, the transcriptional regulation and the gene sets required by K. pneumoniae to survive in disparate environments are not clear. The overarching goal of the proposed research program is to experimentally address whether there are growth (fitness) differences between K. pneumoniae lineages in disparate conditions, ultimately to provide functional insights into its ecological niches and its ability to maintain or transfer AMR genes. Our hypothesis is that the transcriptional and genetic networks in MDR lineages allow these strains to tolerate a wider range of growth conditions and to maintain AMR compared to hypervirulent lineages. We will test this hypothesis using comparative genomics, transcriptomics, fitness assays and phenotyping of different K. pneumoniae clonal types sampled from diverse environments. We will tackle three short-term questions over the next five years: (1) How do different K. pneumoniae strains grow and maintain AMR genes across diverse environments? (2) What is the transcriptional regulation that allows K. pneumoniae to survive in these disparate conditions? and (3) What are the sets of genes essential for K. pneumoniae to survive and maintain AMR genes in those environments? The proposed research will provide insights into the metabolic potential of K. pneumoniae and enhance our understanding of its role in maintaining and distributing AMR genes from environmental sources. This innovative work will provide the first comprehensive functional characterization of both K. pneumoniae MDR and hypervirulent strains, ultimately developing better intervention strategies to prevent K. pneumoniae as an AMR trafficker. Importantly, our study will provide insights into potential mechanisms by which K. pneumoniae with both hypervirulence and multi-drug resistance may arise. These results will allow us to thwart the emergence of hypervirulent K. pneumoniae superbug and will be of interest to clinical and One Health researchers working on AMR.